2-cyano-3-desoxy androstane derivatives and process therefor



. 3 080,401 2-CYANO-3-DESOXY AZNDROSTANE DERIVATIVES AND PROCESSTHEREFOR Albert Bowers, John Edwards, and James C. Grr, Mexico City,Mexico, assignors, by mesne assignments, to Syntex Corporation, acorporation of Panama No Drawing. Filed Mar. 1, 1962, er. No. 176,826

Claims priority, application Mexico, Aug. 31, 1961 21 Claims. (Cl.260-3975) The present invention relates to novelcyclopentanophenanthrene derivatives and to a process for the productionthereof.

More particularly the present invention relates to 2- cyano-3-desoxyandrostane derivatives.

The novel compounds object of the present invention are represented bythe following formulas:

In the above formulas R represents hydrogen or a hydrocarbon carboxylicacyl group of less than 12 carbon atoms; R represents hydrogen, loweralkyl, lower alkenyl or lower alkynyl; R represents hydrogen or methyland R represents hydrogen or methyl. The wavy line indicates the cyanogroup may be in the a or [i steric configuration.

The acyl group is derived from hydrocarbon carboxylic acids containingless than 12 carbon atoms which 'may be saturated or unsaturated, ofstraight, branched, cyclic or cyclic-aliphatic chain, aromatic and maybe substituted by functional groups such as hydroxy, alkoxy containingup to 5 carbon atoms, acyloxy contain- .ing up 0t 12 carbon atoms,nitro, amino or halogen.

Typical ester groups are the acetate, propionate, enanthate, benzoate,trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate,aminoacetate and fl-chloropropionate.

The compounds represented by the above formulas, are anabolic-androgenicagents with a favorable anabolicandrogenic ratio. In addition, they areappetite stimulants with anti-estrogenic, anti-gonadotrophic, bloodcholesterol lowering and anti-fibrillatory properties.

' These compounds also relieve premenstrual tension, depress the centralnervous system and suppress the output of the pituitary gland.

The novel compounds of the present invention are prepared by the processillustrated by the following equaspanner Patented, Mar. 5, 19fi3 on on a..R1 R. IQ 1. lj I NC- NC- I i (W) 5 (III) on l..-R$ n i I NC-- l In theabove formulas R, R R and R have the same meaning as previously setforth.

In practicing the process outlined above, the starting compound, whichis a 2-formyl-A -androsten-1713-01 derivative or the 19-nor derivativethereof (1), (Bowers et a1. copending application Serial No. 128,974filed Aug- 11st 3, 1961), is treated with hydroxylamine hydrochloride inthe presence of pyridine, thus alfording the corresponding aldoxime(II). The latter compound is treated with acetic anhydride and sodiumacetate, at reflux temperature, for a period of time of the order of .2,hours thus giving the respective Z-cyano-M-androsten 17,6-01 derivative(III). When the 17p-hydroxyl is secondary (R =H),.there is obtained thecorresponding 17- acetate which upon conventional saponification with analkali metal hydroxide yields the respective l7B-free alcohol. Catalytichydrogenation of the later compound aifords the corresponding saturated2,8-cyano androstan- 17,8-01 derivative (IV), which upon treatment in abasic medium gives the corresponding 2u-cyano compound (V).

The compounds represented by Formulas III and IV wherein R, R and R arehydrogen, are conventionally acylated in pyridine with an acylatingagent, such as an anhydride derived from a hydrocarbon carboxylic acidof the type described hereinbefore, thus giving the corresponding17-acylates.

The compounds represented by formulas III and IV wherein R is hydrogenand R and R are a lower hydrocarbon residue, are conventionally acylatedwith excess acylating agent in the presence of p-toluenesulfonic acid togive the corresponding 17-acylates.

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

Example I A mixture of 5 g. of 2-formyl-A -androsten-17B-ol, 6 cc. ofpyridine, 40 cc. of ethanol and 1.5 g. of hydroxylamine hydrochloridewas refluxed for 30 minutes and cooled in ice. The formed precipitatewas collected, washed with hot water and dried, thus giving the oxime of2-formyl-A -androsten--01.

Following the same procedure there were treated the starting compoundsunder I, to give the corresponding oximes under II.

2-tormyl-17a-methy1-A -androsten- 2-f o i i g i-l7a-ethyl-A -andrsten-2d)rmyl-l7zx-vinyl-A -androsten- Mil in yi-l7a-ethinyl-A -androsten-2-1i3rihyl-19-nor-A -androsten-17B-ol 2-formyl-17a-methy1-19-n0r-A Theoxime of 2-formyl-l7a-methyl- M-androsten-NB-ol.

The oxime cl 2-formyl-17zx-ethyl- N-androsten-l'ZB-ol. The oxime of2-formyl-17a-viny1- N-androsten-Nfl-ol. The oxime of Z-iormyl-lM-ethmyl-N-androsten-Ufi-ol.

The oxime or" 2-iormyl-19-nor-A' androsten-Ufl-ol.

The oxime of 2-r'ormyl-l7a-methylandrosten-UB-ol.2-iormy1-17a-ethinyl-19-nor-A androsten-Hfi-ol.

1Q-nor-N-androsten-l76-01. The oxime of 2-formyl-l7a-ethmyll-nor-N-androsten-l75-01.

Example II I II The oxime or Mormyl-lm-methyl- M-andrcsten-HB-ol. Theoxime of 2-tormyl-17a-ethyl- 2eyano-17a-methyl-A -androsten- The crimeof 2-formy1-17a-vtny1- N-androsten-NB-ol.

The oxime ct 2-iormyl-17a-ethiny1- A -androsten-17B-ol.

The oxime 0i 2-formyl-19-nor-A androsten-17fi-01.

The oxime of 2-tormyl-17a-methyl- 19-nor-A-androsten-17B-ol.

The oxime of 2-lormyl-17a-ethiny1- lg-nor-N-androste11-17B-o1.

Z-cyano-lQ-nor-N-androsten-17B-o1 acetate.

Z-eyano-lM-methyl-IQmar-A androsten-l'iB-ol.

Example I]! 2 g. of 2-cyano-A -androsten-1713-01 acetate was dissolvedin 50 cc. of methanol and treated with 5 cc. of a 4% aqueous solution ofpotassium hydroxide; the reaction mixture was stirred for 1 hour underan atmosphere of nitrogen at 0 C.; the mixture was neutralized withacetic acid and the methanol distilled under reduced pressure. Theresidue was triturated with water and the solid collected, washed withwater, dried and recrystallized from ethyl acetate-methanol, thusproducing 2-cyano-A androsten-l7 3-ol.

By the same procedure there was treated 2-cyanol9-nor-A-androsten-175-01 acetate to give 2-cyano-l9-nor- A -androsten-flfi-ol.I

Example IV A suspension of 0.5 g. of 5% palladium on carbon catalyst in50 cc. of methanol was hydrogenated for BO-minutes. A solution of 2 g.of 2-cyano-A -androsten- 175-01 in 200 cc. of methanol was added to thecatalyst and stirred under a hydrogen atmosphere until the uptake ofhydrogen ceased. After removal of the catalyst by filtration thesolution Was evaporated and the crude residue was purified bycrystallization from methylenechloride-hexane, thus givingZfl-cyano-androstan-17 8-01.

Following the above procedure there were treated 2-cyano-17u-methy1-A-androsten-175-01, 2-cyano-17a-ethy1-A -androsten-17B-ol,Z-cyano-l9-nor-A -androsten-17e- 01 and 2-cyano-l7a-methyl-19-nor-A-androsten-175-01 aflording correspondingly 28-cyano-l'le-rnethyl-androstan- 175-01,Zfl-cyano-17a-ethyl-androstan-17,6-01, ZB-cyano-19-nor-androstan-l7/8-ol and2fi-cyano-17a-methyl-l9-norandrostan-17fl-ol.

4 Example V 1 g. of ZB-cyano-androstan-l75-01 was dissolved in 20 cc. ofmethanol containing 0.2 g. of potassium hydroxide and the mixture waskept at room temperature overnight, poured into water and extracted withmethylene chloride. Evaporation of the methylene chloride solution andcrystallization of the residue from acetone-hexane yielded2rx-cyano-androstan-175-01.

When applying the foregoing technique toZfl-cyanol7a-methyl-androstan-l718-01,2fi-cyano-l7a-ethyl-androstan-l7B-ol, ZB-cyano-l9-nor-androstan-17fi-o1and 2,6- cyano-17a-methyl-19-nor-androstan-l7B-ol there wererespectively obtained Zea-cyano-l7u-methyl-androstan- 175-01,2a-cyano-l7a-ethyl-androstan-176-01, Zea-cyano- 19-nor-androstan-17fi-o1and Zea-cyano-17a-methyl-19-norandrostan-17/3-ol.

Example VI A mixture of 1 g. of 2-cyano-A -androsten-l7,9-01, 4 cc. ofpyridine and 2 cc. of propionic anhydride was kept at room temperatureovernight, poured into ice water, the formed precipitate was filtered,washed with water and dried. Crystallization from acetone-hexane gave2-cyano-A -androsten-17/3-ol-propionate.

By the same technique there were treated 2,8-cyanoandrostan-IZB-ol,2,8-cyano-l9-nor-androstan-176-01, 2-cyano-19-nor-A -androsten-17 3-01,2a-cyano-androstan-l7 3- 01 and 2a-cyano-19-nor-androstan-l7B-ol,yielding respectively Zfl-cyano-androstan-175-ol-propionate, ZB-cyano-19-nor-androstan-17 8-o1-propionate, 2-cyano-19-nor-Aandrosten-l7p-ol-propionate, 2u-cyano-androstan-175-01- propionate andZea-cyano-19-nor-androstan-17fi-ol-propionate.

Example VII Following the procedure of the foregoing example, exceptthat propionic anhydride was substituted by caproic anhydride,cyclopentylpropionic anhydride and benzoic anhydride, there werecorrespondingly obtained the caproates, cyclopentylpropionates andbenzoates of the starting compounds mentioned in the said example.

Example VIII To a solution of 5 g. of 2-cyano-17a-methyl-A-androsten-l7fi-ol in cc. of anhydrous benzene there were added 1 g. ofp-toluenesulfonic acid and 10 cc. of acetic anhydride and the mixturewas allowed to stand for 24 hours at room temperature, poured into iceand water, and the resulting mixture stirred to effect hydrolysis of theexcess anhydride. The benzene layer was separated and washed with 10%sodium carbonate solution and water. Drying, evaporation andcrystallization of the residue from ether-hexane produced2-cyano-17ct-methyl- A -androsten-17,6-01-acetate.

The starting compounds under I were acetylated by the above technique,yielding the corresponding products under II.

I II

2-cyano-l7a-vinyl-A -androsten- 2-cyano-17a-ethinyl-A -androsten-2-eyano-l7a-rnethyl-l9hor-A androsten-17B-ol.

2-cyan0-17a-ethinyl-19-n0r-A androsten-UB-ol.

ZB-esgmro-lM-methyl-androstanl 2B-cyano-17a-ethy1-androstan- 176-01.2a-cyano-17o4-rnethyl-19-n0randrostan-HB-ol.21-cyano-17a-methyl-androstan- 176-01. methyl-androstan-l? -ol.2az-eyano-l7a-ethyl-androstan- 17-acetate of 2a-cyano-1 7a- -01.ethyl-androstan-Ufi-ol.

5 Example IX The starting compounds mentioned in the preceding examplewere treated following the procedure described in the same example,except that acetic anhydride was substituted by propionic anhydride,caproic anhydride and cyclopentylpropionic anhydride thus affording thecorre sponding l7-propionates, 17-caproates and 17-cyclopenty1-propionates.

We claim:

1. A compound of the following formula:

R. of)

psycho-euro 9. 2-cyano-A -androsten-17/8-ol. 10. A compopund of thefollowing formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is amember of the group consisting of hydrogen and lower alkyl and R isselected from the group consisting of hydrogen and methyl.

ll. Zfl-cyano-androstan-1713-01.

l2. 21i-cyano-l7a-methyl-androstan-17 8-01.

l3. ZB-cy-ano-17a-ethyl-androstan-173-01.

14. ZB-cyano-l9-nor-androstan-17 8-ol.

15. 2(3-cyan0-Hot-methyl-l9-nor-androstan-l7fl-ol.

16. 2ot-cyanorandrostan-l7 8-ol.

l7. Za-cyano-17et-methy1-androstan-1713-01.

18. Zea-cyano-17u-ethyl-androstan-175-01.

19. Zea-cyano-l9-nor-androstan-17B-ol.

20. Zea-cyano-Not-methyl-19-nor-androstan-17fi-ol.

21. In the process for the production of 2-cyano-A androstenederivatives, the step which comprises treating the aldoxime of thecorresponding 2-formyl-A -andro stene, with sodium acetate in aceticanhydride to give .the 2-cyano-A -a-ndr ostene derivative.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: